Comparing the Seizure-Induced Impairment of Short-Term Plasticity in Dorsal and Ventral Hippocampus in Kindled Mice

There are many differences among dorsal and ventral hippocampal neural circuits that affect the synaptic plasticity. In this study we compared the occurrence of short-term plasticity in the field excitatory post synaptic potentials (fEPSP) in dorsal and ventral hippocampal CA1 area following kindled seizures. Animals (male C57 B6/J mice, 12 weeks of age) were kindled by intraperitoneal injections of pentylenetetrazole (PTZ) and fEPSPs were recorded from dorsal and ventral hippocampal slices. Short-term plasticity was evaluated by measuring fEPSP-slope and fEPSP-area following paired-pulse stimulation delivered at three inter-pulse intervals (20, 80 and 160 ms). Obtained results showed that in control slices fEPSP-slope was greater in ventral- compared to dorsal hippocampus, but there was no difference in fEPSP-area among two regions. In hippocampal slices of kindled animals, fEPSP-slope was similar in dorsal and ventral regions, but fEPSP-area was greater in ventral- compared to dorsal hippocampus. In addition, fEPSP-area was greater in kindled compared to control group only in ventral hippocampus. PTZ kindled slices showed impaired short-term facilitation and the paired-pulse index was reduced only at dorsal hippocampal slices. Kindling had no significant effect on paired-pulse ratio in ventral hippocampal slices. Our findings indicated that the seizure occurrence affected the neural activity of hippocampus in a regional dependent manner. Although kindling increased fEPSP-area in ventral hippocampus, kindling-induced changes in short-term synaptic plasticity was significant only in dorsal hippocampal slices compared to control group. The difference in the responses of hippocampal dorsal and ventral poles has to be considered in the future researches.

The modulation of Group I metabotropic glutamate receptor on synaptic transmission efficiency in the Primary Visual Cortex of Monocular Deprivation Amblyopia Rat

Background :The occurrence of amblyopia is closely related to the glutamate receptors in visual cortex. The expression of metabotropic glutamate receptor 1 (mGluR1) in the visual cortex of rats with amblyopia has been proved to decrease, however, the role of mGluR1 in the synaptic transmission of visual cortex is not clear. This study aimed to investigate the effect of group I mGluR on the synaptic transmission efficiency in the primary visual cortex of monocular deprivation amblyopia rat. Methods The 14-day-old rads were rangomly divided intonormal control group and form-deprivation group,with 8 rats in each group. The eyelids of the left eye were sutured to establish the monocular form- deprivation amblyopia rat model,The rats visual cortex slices were prepared and incubated in artificial cerebrospinal fluid . Four groups of drugs that it is 3,5-dihydroxyphenylglycine( DHPG), LY367385, 2-methyl-6( phenyl acetylene) pyridine hydrochloride( MPEP) and DHPG, LY367385and MPEP and DHPG were added to every group, respectively.The extracellular recording technique was used to record the field excitatory postsynaptic potential (fEPSP) in the visual cortex. Results: After application of DHPG, the fEPSP-slope of the visual cortex was significantly increased in both normal rats and monocular deprivation amblyopia rats (P<0.001), but the increase of normal group was significantly higher than that of amblyopia group (P<0.05). Application of LY367385, a selective mGluR1 blocker or Application of MPEP, an mGluR5 blocker can partially reduce the DHPG-induced fEPSP-slope in both normal group and amblyopia group. Conclusions:These results demonstrate that the effect of modulation of group I mGluR (mGluR1, 5) on the synaptic transmission was reduced in the visual cortex of monocular deprivation amblyopia rat. found that agonist DHPG of Group I mGluRs increased synaptic transmission efficiency of neurons in visual cortex of normal rats and monocular form deprivation rats.

Chemogenetic activation of excitatory neurons alters hippocampal neurotransmission in a dose-dependent manner

Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic tools are extensively used to manipulate neuronal activity in a cell-type specific manner. Whole-cell patch-clamp recordings indicate membrane depolarization, coupled with increased neuronal firing rate, following administration of the DREADD ligand, Clozapine-N-Oxide (CNO) to activate the Gq-coupled DREADD, hM3Dq. Although hM3Dq has been used to enhance neuronal firing in order to manipulate diverse behaviors, often within thirty minutes to an hour post-CNO administration, the physiological effects on excitatory neurotransmission remain poorly understood. We investigated the influence of CNO-mediated hM3Dq DREADD activation on distinct aspects of hippocampal excitatory neurotransmission at the Schaffer collateral-CA1 synapse in hippocampal slices derived from mice expressing hM3Dq in Ca2+/calmodulin dependent protein kinase α (CamKIIα)-positive excitatory neurons. Our results indicate a clear dose-dependent effect on fEPSP slope, with no change noted at the lower dose of CNO (1 µM) and a significant, long-term decline in fEPSP slope observed at higher doses (5-20 µM). Further, we noted a robust theta burst stimulus (TBS) induced long-term potentiation (LTP) in the presence of the lower CNO (1 µM) dose, which was significantly attenuated at the higher CNO (20 µM) dose. Whole-cell patch clamp recording revealed both complex dose-dependent regulation of excitability, and spontaneous and evoked activity of CA1 pyramidal neurons in response to hM3Dq activation across CNO concentrations. Our data indicate that CNO-mediated activation of the hM3Dq DREADD results in dose-dependent regulation of excitatory hippocampal neurotransmission, and highlight the importance of careful interpretation of behavioral experiments involving chemogenetic manipulation.

Abstract TP112: Role of Renexin, a Mixed Compound of Ginkgo Biloba Extract and Cilostazol, for Synaptic Plasticity in Hippocampus of Rat Model of Chronic Cerebral Hypoperfusion

The impairment of cognitive function such as memory and attention has been recognized in patients with chronic mild cerebral ischemia. The hippocampal memory and long-term potentiation (LTP), a cellular correlate of learning and memory, were impaired by chronic cerebral hypoperfusion induced by permanent, bilateral occlusion of the common carotid artery (2VO). Objectives: The purpose of present study was to evaluate the effects of renexin on the impaired LTP and expression of mRNA genes involving neuronal plasticity in the rat 2 VO model. Methods: Adult male Sprague-Dawley rats were randomly divide three experimental groups into:1) Sham without 2VO, 2) 2VO+vehicle, 3) 2VO+renexin. The permanent ligation of bilateral common carotid arteries was performed to elicit chronically lower blood flow to the brain. Animals were treated with oral administration of renexin(gingko biloba 20 mg/kg/day + cilostazol 25 mg/kg/day) or vehicle every day from1 day after surgery for 3 weeks. We recorded LTP induced by brief high frequency stimulation to the Schaffer collateral-CA1 pathway of the hippocampus under anesthesia in vivo. Two hours after induction of LTP, the animal was sacrificed and the hippocampus was isolated for quantitative detection of mRNA for BDNF, Arc, Egr-1 and CREB using quantitative real-time RT-PCR technique. Results: Animals of 2VO+vehicle group showed a highly significant deficit in LTP induction (15 ± 3% of control fEPSP slope; n= 7; P< 0.01) 3 weeks after 2VO. On the other hand, daily oral administration of renexin showed the marked preservation of LTP induction (98 ± 17% of control fEPSP slope; n =7; P< 0.01). On the real-time RT-PCR analysis, a significant reduction of CREB, Arc and BDNF mRNA expression was observed in the hippocampus of 2VO+vehicle group compared with that of sham group (P< 0.01). In contrast, renexin treatment increased significantly the expression of these mRNAs in the hippocampus compared with that of 2VO+vehicle group (P< 0.05). Conclusion: These results suggest that daily oral administration of renexin can ameliorate cognitive deficit through the preservation of synaptic plasticity on the level of neural circuit in rodent model of chronic cerebral hypoperfusion.

Fimbria-Fornix Lesions Compromise the Induction of Long-Term Potentiation at the Schaffer Collateral-CA1 Synapse in the Rat In Vivo

Although bilateral fimbria-fornix (FF) lesioning impairs spatial performance in animals, the literature is equivocal regarding its effects on hippocampal long-term potentiation (LTP). We examined the effects of FF lesioning on LTP induction in the Schaffer collateral–CA1 pathway in vivo with a protocol that delivered theta burst stimulation (TBS) trains of increasing length until a sufficient length was reached to induce LTP of the monosynaptic field excitatory postsynaptic potential (fEPSP). Experiments were performed in urethan-anesthetized Long-Evans rats either 4 or 12–16 wk after lesioning. In sham-operated controls, TBS trains ranging from 4 to 12 bursts were sufficient to induce robust LTP [170 ± 10% (mean ± SF) of control fEPSP slope; n = 8]. Four-week post -FF-lesioned animals also displayed clear LTP (167 ± 12% of control fEPSP slope; n = 4) that did not differ from the shams ( P > 0.05). In contrast, animals in the 12- to 16-wk post-lesion group showed a highly significant deficit in LTP induction (95 ± 3% of control fEPSP slope; n = 8; ≤28 burst TBS trains tested; P < 0.001 vs. sham- and 4-wk post-FF-lesion groups). Other quantitative measures of synaptic excitability (i.e., baseline fEPSP slope and input-output relation) did not differ between the sham- and the 12- to 16-wk post-FF-lesion groups. These results indicate that the FF lesion leads to an enduring defect in hippocampal long-term synaptic plasticity that may relate mechanistically to the cognitive deficits characterized in this model.

Enhanced Adenosine A2A Receptor Facilitation of Synaptic Transmission in the Hippocampus of Aged Rats

Adenosine either inhibits or facilitates synaptic transmission through A1 or A2A receptors, respectively. Since A2A receptor density increases in the limbic cortex of aged (24 mo) compared with young adult rats (2 mo), we tested if A2A receptor modulation of synaptic transmission was also increased in aged rats. The A2A receptor agonist, CGS21680 (10 nM), caused a larger facilitation of the field excitatory postsynaptic potential (fEPSP) slope in hippocampal slices of aged (38%) than in young rats (19%), an effect prevented by the A2A receptor antagonist, ZM241385 (20 nM). In contrast to young rats, where CGS21680 facilitation of fEPSPs is prevented by the protein kinase C inhibitor, chelerythrine (6 μM), but not by the protein kinase A inhibitor, H-89 (1 μM), the CGS21680 -induced facilitation of fEPSP slope in aged rats was prevented by H-89 (1 μM) but not by chelerythrine (6 μM). Also, in contrast to the β–receptor agonist, isoproterenol (30 μM), CGS21680 (100–1,000 nM) enhanced cAMP levels in hippocampal nerve terminals of aged but not young rats. Finally, we observed a significant increase of both the binding density of [3H]CGS 21680 and the [3H]ZM241385 as well as of the anti-A2A receptor immunoreactivity in hippocampal nerve terminal membranes from aged compared with young rats. This shows that A2A receptor-mediated facilitation of hippocampal synaptic transmission is larger in aged than young rats due to increased A2A receptor density in nerve terminals and to the modified transducing system operated by A2A receptors, from a protein kinase C mediated control of A1 receptors into a direct protein kinase A dependent facilitation of synaptic transmission.

Evoked Responses of the Dentate Gyrus During Seizures in Developing Gerbils With Inherited Epilepsy

When they are 1–2 mo old, domesticated Mongolian gerbils begin having initially mild seizures which become more severe with age. To evaluate the development of this increasing seizure severity, we obtained field potential responses of the dentate gyrus to paired-pulse stimulation of the perforant path during seizures. In 18 gerbils that were 1.5–8.0 mo old, 73 seizures were analyzed. We measured population spike amplitude, the slope of the field excitatory postsynaptic potential (fEPSP), and the population spike amplitude ratio (2nd/1st) to evaluate excitatory and inhibitory synaptic processes. In gerbils <2 mo old, exposure to a novel environment was followed by an increase in population spike amplitude and then by seizure onset, but population spike amplitude ratio and fEPSP slope remained at baseline levels, and multiple population spikes were never evoked. As previously reported for chronically epileptic gerbils, these findings provide little evidence of a disinhibitory seizure-initiating mechanism in the dentate gyrus when young gerbils begin having seizures. In young gerbils evoked responses changed little during the behaviorally mild seizures. In contrast, most seizures in older gerbils included generalized convulsions, postictal depression, and evoked responses that changed dramatically. In older gerbils, shortly after seizure onset the dentate gyrus became hyperexcitable. Population spike amplitude and fEPSP slope peaked, and multiple population spikes were evoked, suggesting that mechanisms for seizure amplification and spread are more developed in older gerbils. Next, dentate gyrus excitability decreased precipitously, and population spike amplitude and fEPSP slope diminished. This period of hypoexcitability began before the end of the seizure, suggesting it may contribute to seizure termination. After the convulsive phase of the seizure, older gerbils remained motionless during a period of postictal depression, and population spike amplitude remained suppressed until the abrupt switch to normal exploratory activity. These findings suggest that the mechanisms of postictal depression may suppress granule cell excitability. The population spike amplitude ratio peaked after the convulsive phase and then gradually returned to the baseline level an average of 12 min after seizure onset, suggesting that granule cell inhibition recovers within minutes after a spontaneous seizure. Although it is unclear whether the seizure-related changes in evoked responses are a cause or an effect of increased seizure severity in older gerbils, their analysis provides clues about developmental changes in the mechanisms of seizure spread and termination.

17β-Estradiol Enhances NMDA Receptor-Mediated EPSPs and Long-Term Potentiation

17β-estradiol enhances NMDA receptor-mediated EPSPs and long-term potentiation. Gonadal steroid hormones influence CNS functioning through a variety of different mechanisms. To test the hypothesis that estrogen modulates synaptic plasticity in the hippocampus, in vitro hippocampal slices from 2-mo-old Sprague-Dawley male rats were used to determine the effect of 17β-estradiol on both N-methyl-d-aspartate (NMDA) receptor-mediated excitatory postsynaptic potentials (EPSPs) through intracellular recordings and long-term potentiation (LTP) through extracellular recordings. Intracellular EPSPs and extracellular field EPSPs (fEPSPs) were recorded from CA1 pyramidal cells by stimulating Schaffer collateral fibers. In intracellular experiments, slices were perfused with medium containing bicuculline (5 μM) and low Mg2+(0.1 mM) to enhance the NMDA receptor-mediated currents and 6,7-dinitroquinoxaline-2,3-dione (DNQX) (10 μM) to block the α-amino-3-hydroxy-5-methyl-4-isoxazoleproprianate (AMPA) receptor-mediated component. The effects of 17β-estradiol on NMDA receptor-mediated activity were excitatory; concentrations >10 nM induced seizure activity, and lower concentrations (1 nM) markedly increased the amplitude of NMDA-mediated EPSPs (both the first and second responses increased during paired pulse stimulation by 180 and 197%, respectively). In extracellular experiments, slices perfused with 17β-estradiol (100 pM) exhibited a pronounced, persisting, and significant enhancement of LTP of both the fEPSP slope (192%) and fEPSP amplitude (177%) compared with control slices (fEPSP slope = 155%; fEPSP amplitude = 156%) 30 min after high-frequency stimulation. These data demonstrate that estrogen enhances NMDA receptor-mediated currents and promotes an enhancement of LTP magnitude.

Acute Intrahippocampal Infusion of BDNF Induces Lasting Potentiation of Synaptic Transmission in the Rat Dentate Gyrus

Messaoudi, Elhoucine, Kjetil Bårdsen, Bolek Srebro, and Clive R. Bramham. Acute intrahippocampal infusion of BDNF induces lasting potentiation of synaptic transmission in the rat dentategyrus. J. Neurophysiol. 79: 496–499, 1998. The effect of acuteintrahippocampal infusion of brain-derived neurotrophic factor (BDNF) on synaptic transmission in the dentate gyrus was investigated in urethan-anesthetized rats. Medial perforant path-evoked field potentials were recorded in the dentate hilus and BDNF-containing buffer was infused (4 μl, 25 min) immediately above the dentate molecular layer. BDNF led to a slowly developing increase of the field excitatory postsynaptic potential (fEPSP) slope and population spike amplitude. The potentiation either reached a plateau level at ∼2 h after BDNF infusion or continued to increase for the duration of experiment; the longest time point recorded was 10 h. Mean increases at 4 h after BDNF infusion were 62.2 and 224% for the fEPSP slope and population spike, respectively. No changes in responses were observed in controls receiving buffer medium only or buffer containing cytochrome C. BDNF-induced potentiation developed in the absence of epileptiform activity in the hippocampal electroencephalogram or changes in recurrent inhibition on granule cells as assessed by paired-pulse inhibition of the population spike. We conclude that exogenous BDNF induces a lasting potentiation of synaptic efficacy in the dentate gyrus of anesthetized adult rats.